Introduction to immunology Biochemistry

Deficiency of carnitine
Inherited CPT-I deficiency affects only the liver.
CPT-II deficiency affects primarily skeletal muscle and, when severe, the liver.
Symptoms Include:
Muscle cramps are precipitated by fasting, exercise and high fat diet.
Severe muscle weakness related to importance of fatty acids as long term energy source and death.
Hypoglycemia and hypo-ketosis
Diet containing MCFAs (milk fat and coconut oil) is recommended since they do not require carnitine shuttle to enter mitochondria.

1. 1- VICTORIA UNIVERSITY KAMPALA - BPHARM STUDENTS PRESENTED BY KAWALYA STEVEN Overview of Im munology

2.  Immunology : is a branch of life science which deals with the cellula r and molecular events occurring in the body after encounters of micro - org anisms and other foreign substances.  Types of Immunoolo gy: 1- Basic Immunology 2- Clinical Immunology 3- Diagnostic Im munology 4- Therapeutic Immunology Definitions

3. WHO Definitions • Immune system = cells , tissues , and molecules that media te resistance to infection s • Immunology = study of structure and function of the immune sys tem • Immunity = resistan ce of a host to pathogens and their toxic effects • Immune response = collective and coordinated resp onse to the introduction of for eign substances in an individual mediated by the cells and molecules of the immune system

4. Roles of the immun e system > Defense against microbes > Defense against the gro wth of tumor cells > kills the growth of tumor cells > Homeostasis > destruction of abnormal or dead cells (e.g. dead red cells or white blood cells , a ntigen-antibody complex )

5. Innate and adaptive immunity • Defense against microbes includes an early response action called innate immunity a nd a later response called as adaptive immunity. • Innate immunity : is also called natural or native immunity a nd provides first line o f defense against any microbial infection in human body. It usually inv olves many cellular and biochemical events that react to microbes and their products in order to clear them from the bod y.

6. Two types of imm unity 1. Innate ( natur al or native) • first line of immune response ( e.g skin, HCl , N.flora ) • relies on mecha nisms that exist before infection 2. Acquired (adaptive) • Second line of response ( if i nnate fails) • relies on mechanisms that adapt after infection • handled by T - and B- lymphocytes • one cell determines one antigen ic determinant

7. I- Innate immu nity • Based on genetic make-up • Relies on already formed components • Rapid response : within minutes o f infection • Not specif ic • same molecules / cells respond to a range of pathogens • Has no memory • same response afte r repeated exposure • Does not lead to clonal expansion

8. • The innate immune resp onses are produced against the specific structures present over the microbes and are common to man y of them . • Thus , they cannot distin guish the minute differences among microbes . • In contrast , adaptive immunity is stimulated by constant exposure of infecti ous agents . • The most characteristic feature of ad aptive immunity , is memory a gainst the repetitive exposure of same pathogen . • Furthermore, it has a capacity to distinguish between fine differences among micro bes and hence also called as spec ific immunity .

9. Innate immune syste m • innate immune syste m are 1) Barriers - skin and outer epithelial surface . 2) Scavenger cells - neutrophils , macrophages , dendritic cell and natural killer cells . 3) Complement s ystem 4) Cytokines 5) Chemical mediators of inflammation

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11. • Mechanical barriers / sur face secretion • skin , acidic pH in stomach , cilia , mucous • Humoral mechani sms • lysozymes, basic proteins, cytokine, Complement, interferons • Cellular defens e mechanisms • natural killer cells neutrophils , macropha ges,, mast cells, basophils, eosinophils

12. NK Cell Basophils & Mast cells

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14. 1- Neutrophils ( polymorphnuclear cells , PMNs , micropha ge) T he majority of blood leukocytes (≈ 70% of total blood leukocytes ). PMN cells are very active phagocytic cells ; however , they are short-lived cells (6- 12 hours ). If there is noinflammatory process , it undergoes apoptosis . Neutrophils are the first cells arrive to the site of inflammation . So n eutrophils are the major cell population in the acute inflamma tion. - Neutrophils die after antigen destruction. Dead PMN and their debris become the primary component of pu s, characteristic of many bacterial infections.

15. 2- Eoisinophil s : ( 6% of blood leukocytes ) H ave the ability to kill large extracellular parasites such as Schistoso ma species. They are also play a major role in allergic disorders . Eosinophils express receptors for a class of antibodie s termed IgE antibodie s . 2- Basophils : (1% of blood leukocytes ) They express high affinity receptors for IgE antibodies . Basophils play a role in host defense against parasite s and in allergic disorders . Their granules contain histamine and heparin . 14

16. 3- Monocytes and macrophages : Are large mononuclear cells (5% to 7 % of the leukocytes ) in the peripheral blood . Monocytes spend 1 to 2 days in the circulation ( their hal f-life is approximately 8.4 hours ), the n cross the endothelium to enter tissues throughout the body, where they res ide for up to several months as macrophages. Both monocytes and macrophages actively sample their environment by phagocytosis and serve as scavengers to remove cellular debris. Monocytes circulati ng mononuclear phagocytes are called monocytes when they leave the circulati on thy called macroghages 15

17. 4- Dendritic Cell : It s acquired its name because it is covered w ith long membrane extensions th at resemble the dendrites of nerve . Found throughout the body, but predominantly i n potential portals of microbial entry (e.g., skin , lung , gastrointestinal tra ct). 1- Conventio nal DCs (cDCs) 2- Plasmacytoid dendritic cells (pDCs). 3- Follicular DC 16

18. • The innate immune system : > P rovides a rapid and initial means of def ense against i nfection , using genet ically programmed receptors that recognize t hese structural features of microbes that are not found in the host . > Such receptors are kn own as ; P attern R ecognition R eceptors ( PRRs ) w hich are found on or in phagocytic cells , which bind t o pathogen associated molecular patterns (PAMPs).

19. PAMPs: are conserved, microbes-specific carbohydrates, proteins, lipids and / or nucleic acid (e.g. lipopolysaccharide , peptidoglycan , etc . ). PRRs binding to PAMPs result in phagocytosis and enz ymatic degradation of the infectious organisms ( Fi g). Pattern recognition receptors engagement can lead to activa tion of the host cell and i ts secretion of antimicrobial substances. PRRs include :

20. 1. Toll - like recept ors (TLRs),: which signals the synthesis and secretion of cytokines to promo te inflammation by recruiting cells . 2. Scavenger receptors : that are involv ed in internalization of bacteria and phagocytosis of h ost cells that are u ndergoing apoptosis . 3. Opsonins : the molecules (C 3a, IgM ), which bind to microbes to f acilitate their phagocytosis.

21. II- Complement system Microbial Proteins The complement is a group of serum p roteins that circulate in an inactive state. A variety of specific and non - specific immunol ogic mechanisms can convert the inactive form of complement proteins into an active form leading to lysis of bacteria , cells and viruses ; promo tion of phagocytosis ( opsonization ); triggering of inflammation ; secretion of immune - regulatory molecules and c learance of immune complex from the circulation . • Note : In the innate immune system , complement ca n be activated by alternative pathway or via the mannan binding lectin ( MBL ) path way

22.  Complement is a co llective term for a system of enzymes and proteins that function in both the inna te and adaptive branches of the immune system as soluble means of protection against pathogens that evade cellular contact.  Regulatory proteins keep the complemen t system in check. In the innate immune system .  Complement can be activated in two ways :  1- via the alternative pathway , in which antigen is recognized by particular cha racteristics of its surface, or via the mannan-binding lectin ( MBL ) pathway .  2- Complement can also be activated in the adaptive immune system via the classical pathway that begins wi th antigen-antibody complexes

23. The Compleme nt System • A defensive system consist ing of over 30 proteins produced by the liver and foun d in circulating blood serum. • Complement kills microbes in three diff erent ways 1. Opsonization 2. Inflammat ion 3. Cytolysis 25

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25. III _ Interfero ns  Type I interferons ( IFNs ) are produced by a subset of dendritic cells ( IFN - α) , by nonleukocytes such as fibroblasts ( IFN - β), and by other cells in response to viral infection.  IFN -α and - β are rapidly produced , within 5 minutes , by cells when viral PAMPs interact with certai n PRRs. Very little is currently known about the signal transduction pathways responsible for expression and secretion of IFN-α and - β .  Secreted type I IFNs induce both virally infected and non - infected cell s to activate numerous antiviral defenses , including RNA - de pendent protein kinase (PKR) and apoptotic ( programmed cell death ) pathways . In addition , IFN -α and - β influence the activi ties of macrophages and DCs.

26. Type 1 interferon response to intracellular microb ial invasion 28

27. • Cytokines are sec reted by leukocytes and other cells and are involved in innate immunity , adaptive immun ity, and inflammation. • Cytokines act in an antigen - non specific manner and are involved in a wide array of biologic activities , ranging from chemotaxis to acti vation of specific cells to induction of broad physiologic changes. • Chemokines area subgroup of cytokines of low molecular weight and particular structu ral patterns that are involved in the chemotaxis (chemical- induced migration) of leukocytes . • The roles of specific cytokines and chemok ines participate in the immune responses . 29 IV - Cytokines and chemokines

28. CYTOKINES – TYPES I. According to activity :  Interleukins  Interferon s  Growths factors  Tumor - necrosis facto rs  Chemokines II . According to the type of producing cells:  Monokines  Lymphokines

29.  Pro - inflammatory : IL - 1 , IL -6, IL -8, TNF - β- i  Immunoregulatory: IL- 1, IL- 10, TGF- β  Th1 type - IL-2, IFN-ɤ  Th2 type - IL -4, IL -5, IL -9, IL - 10, IL - 13 III. According to participation in immune response

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